(PQ10) Do microbiota alter the epigenetic landscape in human genome

(PQ10) 微生物群会改变人类基因组的表观遗传景观吗

• 批准号: 9171885
• 负责人: Alex Y Strongin
• 金额: $ 25.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-13 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171885
• 关键词: Aberrant DNA Methylation; Address; Affect; Antibiotic Therapy; Bacteria; Benign; Biology; Cancer Biology; Cell Nucleus; Cell Wall; Cells; Chromosome Mapping; Chronic; Clinical; Colon; Colorectal Cancer; CpG Islands; CpG dinucleotide; Cytolysis; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; Data; Development; Disease; Enzymes; Epigenetic Process; Epithelial Cells; Evolution; Exploratory/Developmental Grant; Funding; Genes; Genetic; Genome; Genomic DNA; Genomics; Germ-Line Mutation; Goals; Habitats; Health; Human; Human Biology; Human Genome; Human body; Immune; Incidence; Individual; Infection; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Methodology; Methylation; Methyltransferase; Modification; Mycoplasma; Mycoplasma Infections; Mycoplasma hyorhinis; Nature; Neoplastic Cell Transformation; Oncogenic; Organism; Osmotic Shocks; Patients; Penicillin Resistance; Phenotype; Positioning Attribute; Probability; Promoter Regions; Property; Proteins; Research; Role; Site; Somatic Mutation; Staging; Stem cells; System; Therapeutic; Tissue Sample; Tissues; Tumor Biology; Work; base; cancer cell; cancer risk; cancer stem cell; cancer therapy; cancer type; data mining; epigenome; genome-wide; human tissue; in vivo; innovation; microbial; microbiome; microbiota; novel; novel diagnostics; pathogen; pathogenic bacteria; precursor cell; prognostic; programs; response; trafficking; tumor; tumorigenesis; tumorigenic

PROJECT SUMMARY This application is in response to RFA-CA-15-009 to propose pioneering approaches to addressing PQ–10 “How do microbiota affect the response to cancer therapies?” Human biology is no longer focused only on human cells. Microbiomes at different body habitats are now considered an essential component of human biology, development, evolution, health and disease. Bacteria of the endogenous flora in the human body outnumber human cells by at least one order of magnitude. A plethora of symbiotic and pathogenic bacteria in different body habitats form the microbiome. Bacteria, including mycoplasmas, internalize and colonize human cells, thereby subverting the immune defense system and antibiotic treatment. Mycoplasmas are the smallest and simplest self-replicating organisms. Over 200 species of mycoplasma are distinguished from ordinary bacteria by their minute size, limited genome, and lack of a cell wall. The absence of a cell wall conveys some unique properties to mycoplasma including their resistance to penicillin and sensitivity to lysis and osmotic shock. The data by us and others imply that mycoplasma infections are associated with some cancer types, including colorectal cancer. This suggests the possible co-existence of mycoplasmas and tumors in vivo that affects the response to cancer therapies, or, alternatively, indicates that mycoplasma infections create a possible roadmap to multi-step malignant transformation via epigenetic reprogramming of the affected normal/stem cells. Our working hypothesis is that chronic mycoplasma infection in the gut eventually leads to epigenetic alterations in epithelial cells that may enhance the likelihood for neoplastic transformation. An alternative, but not an exclusive hypothesis, is that the mycoplasma infection accelerates an already on-going tumorigenesis through the induction of additional epigenetic abnormalities. Our goals are to pursue this innovative hypothesis. Our R21 program is based on volumes of our innovative experimental data characterizing epigenetic abnormalities, which are aberrantly introduced in the human genome by mycoplasmal 5-methylcytosine-DNA methyltransferases. Our Specific Aims are: (1) Demonstrate the presence of the aberrant, de novo genomic DNA methylation in host cells infected by M. hyorhinis, and (2) Determine the incidence of the genomic material of Mycoplasma hyorhinis and other mycoplasma species in tumor and normal human tissue samples. We are confident that our proposed studies will lead to paradigm- shifting results in host-pathogen interactions, human epigenetics and cancer onset, and that our project will have wide-ranging ramifications. Additionally, this knowledge will lead to novel diagnostic and prognostic approaches and therapeutic regiments in patients at risk of cancer development.

项目概要 本申请是为了响应 RFA-CA-15-009，提出解决 PQ-10 问题的开创性方法 “微生物群如何影响癌症治疗的反应？”人类生物学不再仅仅关注 人体细胞。不同身体栖息地的微生物组现在被认为是人类的重要组成部分 生物学、发育、进化、健康和疾病。人体内内源性菌群的细菌 数量比人类细胞至少高一个数量级。体内存在大量的共生菌和病原菌 不同的身体栖息地形成了微生物组。细菌，包括支原体，内化并定植于人类 细胞，从而破坏免疫防御系统和抗生素治疗。支原体是最小的 和最简单的自我复制生物体。支原体有200多种，与普通支原体不同 细菌体积微小、基因组有限且缺乏细胞壁。细胞壁的缺失传达了一些信息 支原体的独特特性，包括对青霉素的耐药性以及对裂解和渗透的敏感性 震惊。我们和其他人的数据表明支原体感染与某些癌症类型有关， 包括结直肠癌。这表明支原体和肿瘤在体内可能共存 影响对癌症治疗的反应，或者表明支原体感染会产生 通过受影响的表观遗传重编程实现多步骤恶性转化的可能路线图 正常/干细胞。我们的工作假设是肠道中的慢性支原体感染最终会导致 上皮细胞的表观遗传改变可能会增加肿瘤转化的可能性。一个 另一种假设（但不是唯一的假设）是支原体感染加速了已经持续发生的疾病 通过诱导额外的表观遗传异常来发生肿瘤。我们的目标是追求这一目标 创新假设。我们的 R21 计划基于大量创新实验数据 表征表观遗传异常，这些异常是通过以下方式异常引入人类基因组的： 支原体 5-甲基胞嘧啶-DNA 甲基转移酶。我们的具体目标是： (1) 展示 被猪鼻支原体感染的宿主细胞中存在异常的从头基因组 DNA 甲基化，以及 (2) 确定猪鼻支原体和其他支原体物种的基因组物质的发生率 肿瘤和正常人体组织样本。我们相信，我们提出的研究将带来范式—— 宿主与病原体相互作用、人类表观遗传学和癌症发病的结果发生变化，我们的项目将 具有广泛的影响。此外，这些知识将带来新的诊断和预后 有癌症发展风险的患者的方法和治疗方案。